Intratumoral heterogeneity is a common characteristic of solid tumors. Due to poor vascularization that leads to hypoxia and reduced glucose supply, cancer cells in the tumor core generally become dormant and more resistant to commonly used chemotherapeutic agents than actively dividing cancer cells in the outer layers. This renders many chemotherapeutic agents ineffective as the resistant tumor cells are never completely eradicated. Therefore, combination therapies that attack both inner and outer regions of the solid tumor are more likely to be effective. We and others recently identified pyrvinium for its anti-tumor activity with selective toxicity against cancer cells under glucose starvation. Subsequently we have synthesized several novel pyrvinium analogs with the similar exquisite specificity in attacking cancer cells under glucose deprivation but with improved drug-like properties. Additionally, we found that pyrvinium/analogs specifically block the transcriptional induction of two potential anti-cancer targets, namely GRP78 (glucose-regulated protein-78) and its analog GRP94, under glucose deprivation. The objective of this proposal is to assess novel analog as single agent and in combination with standard of care (Taxol and hypoglycemia-mimicking agent 2-deoxygluocse (2DG) in vivo to treat human non-small cell lung (NSCL) cancer in xenograft models. Taxol is highly effective in eradicating actively dividing cancer cells at the outer layer of the solid tumor. It also inhibits new blood vessel formation, thus increasing glucose deprivation within the core of the tumor, which could potentially further enhance the effect of pyrvinium/ analogs. 2DG is considered nontoxic agent and is also currently under clinical evaluation for cancer treatment in combination with other chemotherapy such as adriamycin and Taxol. It can potentially create artificial glucose deprivation environment in tumor and sensitize tumors to pyrvinium/analogs. In the proposed studies, we will first assess the systemic drug exposure in order to select the lead pyrvinium analog, route of administration and dose regimen for in vivo efficacy studies. Next, we will evaluate the anti-tumor activity of of pyrvinium analog as single agent and in combination therapy of Taxol and 2DG in A549 and NCI-H460 xenograft models of lung cancer, and compare the results to that of standard of care. The enhanced anti- tumor activity and/or increased therapeutic window observed in these studies would demonstrate the feasibility of a new agent or a new combination therapy based on pyrvinium analogs as a potentially new solid tumor treatment paradigm. PUBLIC HEALTH RELEVANCE: The inner core of most solid tumors is generally deprived of nutrients such as glucose and oxygen. Hence cancer cells in the core region become dormant and develop resistance to many chemotherapeutic agents. We and others identified pyrvinium, an antihelminthic medicine, for its unique preferential cytotoxicity to cancer cells under glucose deprivation and anti-tumor activity in vivo. We further synthesized and evaluated several pyrvinium derived analogs with improved "drug" like properties. We hypothesize that these new pyrvinium analogs would significantly enhance anti-tumor activity as a single agent or in combination with standard of care chemotherapeutic agents and hypoglycemia-mimicking agent against solid tumors. The following proposal outlines studies to test this hypothesis. The positive outcomes from the proposed studies may lead to the discovery of a novel class of agents with unique anti-tumor properties, as well as new combination strategies, for the treatment of solid tumors. [unreadable] [unreadable] [unreadable]